Selective Antagonists Of NMDA Receptor GluN2C/GluN2D Subunits And The Mechanism Of Anti-depression

Due to the high incidence of depression and the great harm to society,the "slow" timeliness of first-line antidepressant drugs has been highlighted.Therefore,the research and development of rapid antidepressant drugs based on new targets and new mechanisms is of great clinical significance.In 2019,a major advance in rapid antidepressant therapy was the FDA approval of(S)-ketamine for the treatment of drug-resistant depression.However,ketamine is a non-competitive NMDA receptor antagonist,and its clinical application is severely limited due to psychosocial side effects such as hallucination,dissociation and addiction.The successful case of ketamine rapid anti-depression makes NMDAR modulator become an important direction in the study of new drugs for rapid anti-depression,but how to reduce mental side effects is still an urgent scientific problem to be solved in the study of new drugs targeting NMDAR.In recent years,a number of studies have shown that NMDAR subunit selective modulators have the potential advantage of lower toxic side effects in their rapid antidepressants.The research group in which I worked as a postgraduate has been engaged in the rapid antidepressant research on the monomers and metabolites of rhizoma anemoniae saponins for many years,and the metabolites with antidepressant activity have been screened out(YY-23).In this paper,animal and cell models were used to investigate the rapid antidepressant effect and pharmacological mechanism of YY-23.The main research conclusions include: 1)efficacy evaluation study,and confirmed that YY-23 has a significant rapid antidepressant effect by using the chronic social failure stress depression model.2)target study,preliminary confirmation of YY-23 as a non-competitive NMDA receptor antagonist,but no obvious effect on a variety of important targets of the monoamine transmitter system.3)selective study of NMDAR subunits.Combining xenopus oocytes and HEK293 cell models,it was found that YY-23 could significantly inhibit the NMDAR channel current containing Glu N2 C and Glu N2 D subunits,but had no obvious effect on the receptors of Glu N2 A and Glu N2 B subunits,indicating that YY-23 had the selective characteristics of Glu N2 C and Glu N2 D subunits.4)regulation mechanism research,due to the NR2 C,mainly in the cerebellum distribution in cortex,hippocampus brain regions only in astrocyte distribution,on the basis of this topic is focused on the NR2 D,subject first RNA-corroborate NR2 D Scope technology is applied to the medial prefrontal regions interneurons specificity expression,application of brain slice electrophysiological technique next clear YY-23 of the medial prefrontal interneurons NMDA has obvious inhibition induced current,prompt YY-23 May be selectively ACTS on the GABA interneurons NMDA receptor,The excitatory pyramidal neurons in the medial cortical limbic region were enhanced in a "de-inhibited" manner,resulting in rapid antidepressant activity.5)successfully constructed Grin2 d gene knockout mice.In this study,the rapid antidepressant efficacy,target screening and mechanism of YY-23,the metabolites of ginsenoside,were preliminarily studied.The results suggested that yy-23 was a selective modulator of NMDAR subunits,and its rapid antidepressant efficacy was obvious,suggesting that YY-23 had a great potential as a potential drug.The results of this study provide a solid foundation for the further preclinical and clinical study of yy-23 rapid antidepressant.